Gastrointestinal electrical stimulation

ABSTRACT

The present invention is directed to a method of regulating gastrointestinal action in a subject using a stimulatory electrode and a sensor to provide retrograde feedback control of electrical stimulation to the GI tract. The invention is further directed to a method for reducing weight in a subject, again using a stimulatory electrode and a sensor to provide retrograde feedback control of electrical stimulation to the stomach. The invention is further directed to a method of providing electrical field stimulation to a gastrointestinal organ, as well as a method of providing an electrical potential gradient in a gastrointestinal organ. Further provided is a method of stimulating the vagus nerve of a subject. Additionally provided is a method of placing a device in the gastrointestinal tract or wall of a subject from the exterior of the subject, using a needle to insert the device.

This application claims priority of U.S. Provisional Patent ApplicationNo. 60/195,977, filed Apr. 11, 2000. This application is a divisional ofU.S. patent application Ser. No. 09/913,556, filed Mar. 27, 2002, nowU.S. Pat. No. 6,826,428 filed as a national stage of PCT/US00/28128which was filed on Oct. 11, 2000.

FIELD OF THE INVENTION

The present invention relates generally to gastrointestinal electricalstimulation, and more particularly to methods for regulatinggastrointestinal action, reducing weight, providing electrical fieldstimulation to a gastrointestinal organ, providing electrical potentialgradient in a gastrointestinal organ, stimulating the vagus nerve, andplacing a device in the gastrointestinal tract or wall.

BACKGROUND OF THE INVENTION

Throughout this application various publications are referenced, many inparenthesis. Full citations for each of these publications are providedat the end of the Detailed Description and throughout the DetailedDescription. The disclosures of each of these publications in theirentireties are hereby incorporated by reference in this application.

Motility is one of the most critical physiological functions of thehuman gut. Without coordinated motility, digestion and absorption ofdietary nutrients could not take place. To accomplish its functionseffectively, the gut needs to generate not just simple contractions butcontractions that are coordinated to produce transit of luminal contents(peristalsis). Thus, coordinated gastric contractions are necessary forthe emptying of the stomach. The patterns of gastric motility aredifferent in the fed state and the fasting state (Yamada et al. 1995).In the fed state, the stomach contracts at its maximum frequency, 3cycles/min (cpm) in humans and 5 cpm in dogs. The contraction originatesin the proximal stomach and propagates distally toward the pylorus. Inhealthy humans, the ingested food is usually emptied by 50% or more at 2hours after the meal and by 95% or more at 4 hours after the meal(Tougas et al. 2000). When the stomach is emptied the pattern of gastricmotility changes. The gastric motility pattern in the fasting stateundergoes a cycle of periodic fluctuation divided into three phases:phase I (no contractions, 40-60 minutes), phase II (intermittentcontractions, 20-40 minutes) and phase III (regular rhythmiccontractions, 2-10 minutes).

Gastric motility (contractile activity) is in turn regulated bymyoelectrical activity of the stomach. Gastric myoelectrical activityconsists of two components, slow waves and spike potentials (Chen andMcCallum 1995). The slow wave is omnipresent and occurs at regularintervals whether or not the stomach contracts. It originates in theproximal stomach and propagates distally toward the pylorus. The gastricslow wave determines the maximum frequency, propagation velocity andpropagation direction of gastric contractions. When a spike potential(similar to an action potential), is superimposed on the gastric slowwave a strong lumen-occluded contraction occurs. The normal frequency ofthe gastric slow wave is about 3 cpm in humans and 5 cpm in dogs. Anoninvasive method similar to electrocardiography, calledelectrogastrography, has been developed and applied to detect gastricslow waves using abdominal surface electrodes (Chen and McCallum 1995).

Abnormalities in gastric slow waves lead to gastric motor disorders andhave been frequently observed in patients with functional disorders ofthe gut, such as gastroparesis, functional dyspepsia, anorexia and etc.(Chen and McCallum 1995). Gastric myoelectrical abnormalities includeuncoupling and gastric dysrhythmia and can lead to significantimpairment in gastric emptying (Lin et al. 1998; Chen et al. 1995a;Telander et al. 1978; You and Chey 1985; Chen and McCallum 1993).Tachygastria (an abnormally high frequency of the gastric slow wave) isknown to cause gastric hypomotility (Lin et al. 1998; Chen et al. 1995a;Telander et al. 1978; You and Chey 1985; Chen and McCallum 1993).

Gastric emptying plays an important role in regulating food intake.Several studies have shown that gastric distention acts as a satietysignal to inhibit food intake (Phillips and Powley 1996) and rapidgastric emptying is closely related to overeating and obesity (Dugganand Booth 1986). In a study of 77 subjects composed of 46 obese and 31age-, sex-, and race-matched nonobese individuals, obese subjects werefound to have a more rapid emptying rate than nonobese subjects (Wrightet al. 1983). Obese men were found to empty much more rapidly than theirnonobese counterparts. It was concluded that the rate of solid gastricemptying in the obese subjects is abnormally rapid. Although thesignificance and cause of this change in gastric emptying remains to bedefinitively established, it has been shown that several peptides,including cholecystokinin (CCK) and corticotropin-releasing factor(CRF), suppress feeding and decrease gastric transit. The inhibitoryeffect of peripherally administered CCK-8 on the rate of gastricemptying contributes to its ability to inhibit food intake in variousspecies (Moran and McHugh 1982). CRF is also known to decrease foodintake and the rate of gastric emptying by peripheral injection (Sheldonet al. 1990). More recently, it was shown that in ob/ob mice (a geneticmodel of obesity), the rate of gastric emptying was accelerated comparedwith that in lean mice (Asakawa et al. 1999). Urocortin, a 40-amino acidpeptide member of the CRF family, dose-dependently and potentlydecreased food intake and body weight gain as well as the rate ofgastric emptying, in ob/ob mice. This suggests that rapid gastricemptying may contribute to hyperphagia and obesity in ob/ob mice andopens new possibilities for the treatment of obesity.

There have been a number of reports on gastrointestinal electricalstimulation for the treatment of gastrointestinal motility disorders inboth dogs and humans (U.S. Pat. Nos. 5,423,872, 5,690,691, and5,836,994; PCT International Publication No. WO 99/30776; Bellahsene etal. 1992; Mintchev et al. 1998; Mintchev et al. 1999; Mintchev et al.2000; Chen et al. 1998; Chen et al. 1995c). These disorders arecharacterized by poor contractility and delayed emptying (by contrastwith obesity) and the aim of electrical stimulation in this setting isto normalize the underlying electrical rhythm and improve theseparameters. In general, this is done by antegrade or forward gastric (orintestinal) stimulation.

Previous work on antegrade gastrointestinal stimulation has been focusedon its effects on a) gastric myoelectrical activity, b) gastricmotility, c) gastric emptying, and d) gastrointestinal symptoms (Lin etal. 1998; Eagon and Kelly 1993; Hocking et al. 1992; Lin et al. 2000a;McCallum et al. 1998; Miedema et al. 1992; Qian et al. 1999; Abo et al.2000; Bellahsene et al. 1992). These studies have conclusively shownthat entrainment of gastric slow waves is possible using an artificialpacemaker. Recent studies have indicated that such entrainment isdependent on certain critical parameters, including the width andfrequency of the stimulation pulse (Lin et al. 1998). It has also beenshown that antegrade intestinal electrical stimulation can entrainintestinal slow waves using either serosal electrodes (Lin et al. 2000a)or intraluminal ring electrodes (Bellahsene et al. 1992).

Obesity is one of the most prevalent public health problems in theUnited States. According to the National Health and NutritionExamination Survey, “overweight” (body mass index or BMI=25.0-29.9kg/m²) adults now represent 59.4% of the male and 50.7% of the femalepopulation in this country, totaling more than 97 million people. Thecorresponding figures for “obesity” (BMI≧230) are about 19.5% for menand 25% for women, involving a total of almost 40 million people.“Morbid obesity” or clinically severe obesity (BMI≧40 or >100 lbs overnormal weight) affects more than 15 million Americans (Kuczmarski et al.1994; Troiano et al. 1995; Flegal et al. 1998; Kuczmarski et al. 1997).The treatment of obesity and its primary comorbidities costs the UShealthcare system more than $100 billion each year (Klein 2000; Martinet al. 1995; Colditz 1992; Wolf and Colditz 1998); in addition,consumers spend in excess of $33 billion annually on weight-reductionproducts and services (House Committee 1990). Moreover, obesity isassociated with an increased prevalence of socioeconomic hardship due toa higher rate of disability, early retirement, and widespreaddiscrimination (Enzi 1994; Gortmaker et al. 1993).

Obesity is a complex, multifactorial and chronic condition characterizedby excess body fat. Obesity results from an imbalance between energyexpenditure and caloric intake. Although the causes of this imbalanceare not completely understood, genetic and/or acquired physiologicevents and environmental factors are important. Recent studies haveshown that approximately a third of the variance in adult body weightsresults from genetic influences (Stunkard 1996). In this regard, muchattention has been paid to leptin, an adipocyte- and placenta-derivedcirculating protein that communicates the magnitude of fat stores to thebrain. A deficiency of leptin (ob/ob) or a defective leptin receptor(db/db) seems responsible for obesity in ob/ob and ob/db mice and obeseZucker rats (Frederich et al. 1995). Various gastrointestinal peptides,such as cholecystokinin, enterostatin and glucagon and neurotransmitters(serotonin) that provide communication between the brain,gastrointestinal tract and adipose tissue also may have an etiologicrole in obesity (Bandini et al. 1990). Possible environmental mechanismsfor obesity involve pharmacologic agents (such as antipsychotic drugsand certain antidepressants), cultural and ethnic factors (Morley 1987),hyperphagia and high fat intake (Sobal and Stunkard 1989), inactivity,and psychological factors, such as overeating resulting from emotionaldistress, including poor mood or depression and low self-esteem (Namnoum1993).

Obesity is a major risk factor for many chronic diseases, includingdiabetes mellitus type II, cardiovascular diseases, reproductivedisorders, certain cancers, gallbladder disease, respiratory disease andother comorbidities, such as osteoarthritis, edema, gastroesophagealreflux, urinary stress incontinence, idiopathic intracranialhypertension, or venous stasis disease of the lower extremities(AACE/ACE Position 1998). Although patients with type II diabetes arenot necessarily obese, weight gain before the development of type IIdiabetes is common (Despres 1993). Obesity is the most powerfulenvironmental risk factor for diabetes mellitus type II (Kissebah et al.1989) and the prevalence of diabetes is 2.9 times higher in overweight(BMI≧27.8 in men and ≧27.3 in women) than in non-overweight subjects 20to 75 years of age (NIH 1985). When this age range is narrowed tobetween 20 and 45 years, this risk is 3.8 times higher (Van Itallie1985). Mortality due to cardiovascular disease is almost 50% higher inobese patients than in those of average weight and is 90% higher inthose with severe obesity (Namnoum 1993). Sixty percent of obesepatients have hypertension (Alpert and Hashimi 1993). Fatty infiltrationof the myocardium, right hypertrophy, excess epicardial fat,abnormalities of ventricular function, and increased left ventricularfilling pressure all seem closely related to the duration of obesity(Nakajima et al. 1985). Obesity has a detrimental effect on femalereproductive function (Thompson 1997). In comparison with normal-weightwomen, obese female patients have a higher mortality rate from cancer ofthe gallbladder, biliary passages, breast, uterus and ovaries (NIH1985). Obese men have a higher rate of mortality from rectal andprostate cancer than nonobese men (NIH 1985). Both obese men and womenhave an increased risk of colon cancer. Obesity is a common cause ofsleep apnea and about 50% to 70% of patients diagnosed with sleep apneaare obese (Douglas 1995). Sleep apnea is associated with an increasedrisk of vehicular accidents and cardiovascular and cerebrovascularincidents (Douglas 1995).

In the past, the success of treatment modalities for obesity wasmeasured by the rate and amount of weight loss. More recently, successis being measured by the ability to achieve and maintain a clinicallyhelpful and significant weight loss and by the salutary effects ofweight loss on comorbidities of obesity. The treatment of obesity can beclassified into three categories: general measures, pharmacotherapy andsurgical treatment.

Typically, an obese patient is first counseled about adopting somegeneral measures such as caloric restriction, behavior therapy andphysical activity. The goal of this program is to integrate positiveeating and physical activity behaviors into the patient's life. Althoughan acceptable weight loss may be achieved with such measures,maintaining weight loss seems to be more difficult, particularly forpatients who were treated with caloric restriction. About 50% ofpatients regain weight within one year after the treatment and almostall patients regain weight within 5 years (AACE/ACE Position 1998).

Pharmacotherapy of obesity has been problematic. Amphetamine derivativessuch as fenfluramine and dexfenfluramine have been commonly used untiltheir recent withdrawal from the market due to the-long-term risk ofcardiovascular effects (Bray and Greenway 1999). A number of otherFDA-approved drugs are currently available for the medical treatment ofobesity. These include sibutramine, diethylpropion, mazindol,phentermine, phenylpropanolamine, orlistat etc. (Bray and Greenway 1999;Hvizdos et al. 1999). Sibutramine, a centrally acting antiobesity agent,was recently approved by the FDA for use up to 1 year. Its clinicalefficacy has been evaluated in about 4,600 patients worldwide (Smith1997). Its adverse events include dry mouth, anorexia and constipation.It has several drug interactions and cannot be used in patients withpoorly controlled or uncontrolled hypertension, severe renal impairment,severe hepatic dysfunction, congestive heart failure, coronary arterydisease, and etc. Diethylpropion, mazindol and phentermine are approvedonly for short-term use and their clinical efficacy is very muchlimited. Diethlpropion, an anorexic agent, is effective in producingweight loss but is indicated for use up to only a few weeks. A clinicaltrial indicated a weigh loss ranging from 6.6 kg to 11.3 kg but 82% ofthe 200 patients did not complete the trial (Le Riche and Csima 1967).Mazindol, structurally related to the tricyclic antidepressant agents,seems to act by blocking norepinephrine reuptake and synapticallyrelease dopamine. It is effective as an appetite suppressant. Loss ofweight of 12 to 14 kg was reported in a one-year study. However, theplacebo group also showed a weight loss of 10 kg (Enzi et al. 1976).Phenylpropanolamine is an over-the-counter drug as an aid in weightreduction. This agent acts on the α₁-receptor and is used systemicallyas an appetite suppressant. In a comprehensive obesity-managementprogram, it was shown an increased weight loss by 0.25 to 0.5 poundweekly in comparison with placebo. However, its effect diminishes after4 weeks (Lasagna 1988; Greenway 1992).

Surgical treatment is typically reserved for patients with morbidobesity (BMI>40) (Consensus Development 1991). Two options are generallyavailable. The first is a restrictive operation designed to make thestomach smaller, such as vertical banded gastroplasty (also calledgastric stapling) which can be done laparoscopically (Doldi et al. 2000;Balsiger et al. 2000). Vertical banded gastroplasty results in a weightloss for at least 2 years (Sagar 1995) but some of the weight lost maybe regained within 5 years (Nightengale et al. 1991). Longer follow-upstudies are not available (Sagar 1995). The second kind of surgery is agastric bypass operation that promotes mal-digestion of ingestednutrients. This includes procedures such as Roux-en-Y gastric bypass orextensive gastric bypass (biliopancreatic diversion) (Institute ofMedicine 1995; Benotti and Forse 1995; Fried and Peskova 1997;Scorpinaro et al. 1996; Scopinaro et al. 1981). Roux-en Y gastric bypassproduces more substantial weight loss than vertical banded gastroplasty(Brolin et al. 1992; Sugerman et al. 1992). This procedure is a morecomplicated gastric bypass that successfully promotes weight loss. Othersurgical approaches include intestinal bypass (effective but associatedwith major complications), jaw wiring (effective while used), andliposuction (cosmetic procedure). The risks involved with surgicaltreatment of morbid obesity are substantial. While the immediateoperative mortality rate for both vertical banded gastroplasty andRoux-en-Y gastric bypass has been relative low, morbidity in the earlypostoperative period (wound infections, dehiscence, leaks fromstaple-line breakdown, stomal stenosis, marginal ulcers, variouspulmonary problems and deep thrombophlebitis in the aggregate) may be ashigh as 10% or more. In the later postoperative period, other problemsmay arise and may require reoperative surgery. Such problems includepouch and distal esophageal dilation, persistent vomiting (with orwithout stomal obstruction), cholecystitis or failure to lose weight.Moreover, mortality and mobidity associated with reoperative surgery arehigher than those associated with primary operations. In the long term,micronutrient deficiencies, particularly of vitamin B₁₂, folate andiron, are common after gastric bypass and must be sought and treated.Another potential result of this operation is the so-called “dumpingsyndrome” which is characterized by gastrointestinal distress and othersymptoms.

A need continues to exist for additional feasible and suitable means totreat obesity. Likewise, a need continues to exist for additionalfeasible and suitable means to treat other gastrointestinal tractdisorders.

SUMMARY OF THE INVENTION

To this end, the subject invention provides a method of regulatinggastrointestinal action in a subject. The method comprises determiningan optimum level of total gastrointestinal action in a subject, thetotal gastrointestinal action including naturally occurringgastrointestinal action and non-naturally occurring gastrointestinalaction; positioning a stimulatory electrode relative to the subject sothat the stimulatory electrode can generate non-naturally occurringgastrointestinal action; positioning a sensor relative to the subject sothat the sensor senses the level of total gastrointestinal action, thesensor being operatively connected to the stimulatory electrode;periodically detecting the level of total gastrointestinal action withthe sensor; and periodically generating non-naturally occurringgastrointestinal action with the stimulatory electrode when the detectedlevel of total gastrointestinal action differs from the optimum leveluntil the detected level of total gastrointestinal action substantiallyequals the optimum level.

The invention further provides a method for reducing weight in a subjecthaving a stomach. The method comprises determining an optimum level oftotal stomach electrical activity in a subject which reduces weight inthe subject, the total stomach electrical activity including naturallyoccurring stomach electrical activity and non-naturally occurringstomach electrical activity; positioning a stimulatory electroderelative to the subject so that the stimulatory electrode can generatenon-naturally occurring stomach electrical activity; positioning anelectrical activity sensor relative to the subject so that theelectrical activity sensor senses the level of total stomach electricalactivity, the electrical activity sensor being operatively connected tothe stimulatory electrode; periodically detecting the level of totalstomach electrical activity with the electrical activity sensor; andperiodically generating non-naturally occurring stomach electricalactivity with the stimulatory electrode when the detected level of totalstomach electrical activity differs from the optimum level until thedetected level of total stomach electrical activity substantially equalsthe optimum level.

Also provided is a method of providing electrical field stimulation to agastrointestinal organ. The method comprises positioning a firststimulatory electrode in a gastrointestinal organ; positioning a secondstimulatory electrode in the gastrointestinal organ, the secondstimulatory electrode being positioned at least about two centimetersfrom the first stimulatory electrode; and electrically stimulating thegastrointestinal organ simultaneously through the first and the secondstimulatory electrodes, wherein one of the first and the secondstimulatory electrodes has a positive polarity and wherein the other oneof the first and the second stimulatory electrodes has a negativepolarity, thereby providing electrical field stimulation to thegastrointestinal organ between the first and the second stimulatoryelectrodes.

Additionally provided is a method of providing electrical potentialgradient in a gastrointestinal organ. The method comprises positioning afirst stimulatory electrode in a gastrointestinal organ; positioning asecond stimulatory electrode in the gastrointestinal organ, the secondstimulatory electrode being positioned at least about two centimetersfrom the first stimulatory electrode; and electrically stimulating thegastrointestinal organ simultaneously through the first and the secondstimulatory electrodes, wherein voltage generated by the firststimulatory electrode differs from voltage generated by the secondstimulatory electrode, thereby providing an electrical potentialgradient in the gastrointestinal organ between the first and the secondstimulatory electrodes.

The invention further provides a method of stimulating the vagus nerveof a subject. The method comprises positioning a stimulatory electrodein a gastrointestinal organ of a subject; and generating electricalcurrent in the gastrointestinal organ of the subject with thestimulating electrode, wherein the electrical current in thegastrointestinal organ of the subject stimulates the vagus nerve of thesubject.

The invention also provides a method of placing a device in thegastrointestinal tract of a subject from the exterior of the subject.The method comprises inserting an end of a needle having an interiorbore from the exterior of a subject into the gastrointestinal tract ofthe subject, the gastrointestinal tract of the subject having a centerdefined by a wall, the wall having a thickness defining an interior walladjacent to the center and an exterior wall, and the end of the needlebeing inserted through the wall into the center of the gastrointestinaltract; inserting a device through the interior bore of the needle,wherein the device has an interior wall engaging means and wherein thedevice is inserted at least until the interior wall engaging meansextends beyond the interior bore of the needle; removing the needle; andretracting the device until the interior wall engaging means engages theinterior wall of the gastrointestinal tract of the subject, therebyplacing the device in the gastrointestinal tract of the subject.Alternatively, the invention provides a method of placing a device inthe gastrointestinal wall of a subject from the exterior of the subject.This method comprises inserting an end of a needle having an interiorbore from the exterior of a subject into the gastrointestinal wall ofthe subject, the gastrointestinal wall defining a center of agastrointestinal tract of the subject, the gastrointestinal wall havinga thickness defining an interior wall adjacent to the center and anexterior wall, and the needle being inserted until the end of the needleis positioned in the thickness of the wall between the interior wall andthe exterior wall; inserting a device through the interior bore of theneedle, wherein the device has an engaging means and wherein the deviceis inserted until the engaging means extends beyond the interior bore ofthe needle into the thickness of the wall; removing the needle;and-retracting the device until the engaging means engages the thicknessof the wall, thereby placing the device in the gastrointestinal wall ofthe subject.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features and advantages of this invention will beevident from the following detailed description of preferred embodimentswhen read in conjunction with the accompanying drawings in which:

FIG. 1 is a general diagram of the gastrointestinal tract of a humansubject;

FIG. 2 illustrates the retrograde electrical stimulation (RGES) of thestomach to retard the propulsive activity of the stomach and slow downgastric emptying;

FIG. 3 illustrates the effects of RGES at a tacygastrial frequency ongastric slow waves and contractions in a healthy dog;

FIGS. 4A-4C illustrate normalization of bradygastria using gastricelectrical stimulation;

FIG. 5 illustrates the effect of gastric pacing on retention of aradionuclide solid meal;

FIG. 6 illustrates food intake in separate sessions with varying amountsof electrical stimulation;

FIG. 7 illustrates symptoms seen in the separate sessions of FIG. 6;

FIGS. 8A and 8B illustrate the effect of RGES at the normal frequency ongastric emptying and slow wave coupling;

FIG. 9 illustrates a typical portable pacemaker in use;

FIG. 10 illustrates gastric pacing in a rat;

FIG. 11 illustrates the effect of RGES on vagal and sympathetic tone;

FIG. 12 is a block diagram of a typical RGES system;

FIG. 13 is a block diagram of an adaptive filter;

FIG. 14 details the structure of the adaptive ARMA filter;

FIG. 15 is a block diagram of a portable stimulator; and

FIG. 16 illustrates the connection of electrodes to a dog stomach.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the “gastrointestinal tract” (GI tract) refers to the“gut” or the “alimentary canal” that is a continuous, coiled, hollow,muscular tube that winds through the ventral body cavity (see FIG. 1).It is open to the external environment at both ends. In a human, it'sorgans (gastrointestinal organs) generally include the mouth, pharynx,esophagus, stomach, small intestine (duodenum, jejunum, and ileum), andlarge intestine (cecum, appendix, colon, rectum, and anal canal). Thelarge intestine leads to the terminal opening, or anus.

The “gastrointestinal wall” refers to the continuous, coiled, hollow,muscular tube that is the gastrointestinal tract. The wall generallydefines the center (lumen) of the GI tract (the hollow portion of thetube). The wall has a thickness defining an interior wall adjacent tothe center of the GI tract and an exterior wall (see FIG. 1 insert).

As used herein, “gastrointestinal action” refers to any GI actions whichare generated by electrical activity. Thus, gastrointestinal actionincludes, for example, gastrointestinal electrical activity,gastrointestinal contractile activity (such as stomach contractileactivity), gastrointestinal motility, gastric emptying, gastrointestinalpressure, gastrointestinal impedence, and afferent nerve activity(including vagal nerve, sympathetic nerves, and spinal nerves).

A subject refers to an animal, including a human, subject. For non-humananimal subjects, the particular structure of the GI tract may differfrom that shown in FIG. 1. For such non-human animal subjects, thegastrointestinal tract, as used herein, refers to that non-humananimal's known GI tract and GI organs.

An “optimum level” refers to a pre-determined target, which isdetermined based on the desired outcome. For example, in RGES (seebelow), the definition of optimization is based on an optimalcombination of efficacy, safety and feasibility. That is, the optimalRGES settings are those that result in a significant reduction in foodintake (efficacy) but do not induce undesired symptoms, such as nauseaor vomiting (safety) with minimal energy (maximally feasible for animplantable device). Iterative adjustments of stimulation parameters aremade to achieve this result. For any particular gastrointestinal action,an “optimum level” or desirable level can be determined by monitoringthe appropriate GI action. As another example, an appropriate amount ofGI pressure at the esophageal sphincter can be determined which preventsreflex of stomach juices into the esophagus, while still allowing thepassage of food items into the stomach. With this predetermined “optimumlevel”, a stimulatory electrode can be established with a sensor tomaintain this optimum level. The optimum level is thus fact and subjectspecific, but readily determinable with routine experimentation, takinginto account the goal of an optimal combination of efficacy, safety andfeasibility.

“Total gastrointestinal action”, refers to the sum total of levels ofany naturally occurring gastrointestinal action and levels of anynon-naturally occurring gastrointestinal action. Naturally occurringgastrointestinal action refers to spontaneous gastrointestinal actionthat is present in a subject prior to a particular treatment.Non-naturally occurring gastrointestinal action refers tonon-spontaneous gastrointestinal action generated by the hand of man orotherwise caused to occur by the particular treatment of the subject. Itis important to note that the non-naturally occurring gastrointestinalaction which is generated and which is non-spontaneous GI action may infact be identical (in a physiological sense, for example) to a naturallyoccurring GI action once it has been generated. For example, a subjectmay have a naturally occurring level of stomach electrical activity of“X”. A stimulatory electrode is positioned to generate a non-naturallyoccurring level of stomach electrical activity of “Y”. The totalgastrointestinal action, which is stomach electrical activity in thisexample, is therefore “X+Y”.

A “stimulatory electrode” refers to a conductor of electricity throughwhich current enters a medium (a subject), whereas a “sensor” refers toa conductor of electricity through which current leaves a medium (asubject). Typically, for gastrointestinal uses, the stimulatoryelectrodes and sensors are constructed of teflon-insulated wires such asare used for cardiac pacing wires. The stimulatory electrode iselectrically connected (i.e., conductively connected) to a source ofelectrical current (often referred to as a pacemaker where a set patternof electrical current is delivered), and the sensor is electricallyconnected to a device for determining the level of electrical current“sensed” by the sensor (an electrical recorder, for example). Thestimulatory electrode is thus used to “generate” electrical current andthe sensor is thus used to “detect” electrical current. Note that thestimulatory electrode can be used to “generate” electrical current,which is itself a defined “gastrointestinal action”, but the generationof electrical current can also produce other gastrointestinal actions(such as, for example, stomach contraction or esophageal pressure). Thelanguage “generating” GI action is thus intended to cover both concepts,i.e. the generation of the initial electrical current and the ultimategastrointestinal action which is “generated” as a result of the current(i.e. the contraction or pressure).

“Operatively connected” is used herein to refer to the connectionbetween the stimulatory electrode and the sensor, and indicates that theoperation of one is connected to the operation of the other. Inparticular, the sensor connects to a device which determines the levelof electrical current sensed by the sensor. A representation of thatlevel is then fed to the source of electrical current that iselectrically connected to the stimulatory electrode. The source ofelectrical current is provided with a programmable computer circuit thatenables the level from the sensor to determine, or dictate, theoperation of the source (i.e., electrical current is generated by thesource and fed through the stimulatory electrode in response to and anin relation to the amount of the level of electrical activity sensed bythe sensor). Thus, the “operatively connected” stimulatory electrode andsensor enable the retrograde feedback concept to occur.

“Positioning” a stimulatory electrode or a sensor refers to placement ofthe stimulatory electrode or sensor on or in a subject. In the exampleof gastrointestinal pacing, the teflon-coated wires which are thestimulatory electrode and the sensor can be “positioned” as shown inFIGS. 9 and 16.

“Periodically” refers to evenly or unevenly spaced time intervals.

“Differs from” refers to a statistically significant variation betweentwo compared values, and therefore does not always require a differencein orders of magnitude. It should be apparent that where small valuesare compared, statistically significant variations can likewise be verysmall, and where large values are compared, statistically significantvariations can be large. Conversely, “substantially equals” refers to astatistically insignificant variation between two compared values.

“Reducing weight” refers to a reduction or decrease in weight of asubject.

“Electrical field stimulation” refers to the generation of an“electrical field”, which indicates that the area of distribution of theelectrical current from the stimulation encompasses the entire areabetween and/or surrounding two or more stimulatory electrodes, and“field” is used to imply that the two or more stimulatory electrodes arepositioned at least about three centimeters apart (thus the term “field”to differ from prior stimulations where the two electrodes of a pair arepositioned in close proximity to one another and do not generate a“field”).

A “device” refers to any suitable item which can readily be and isdesirable to be placed in the GI tract. Such devices can include, forexample, stimulatory electrodes and sensors for use in the RGES methodof the subject invention. Such devices could also include a smallballoon to be used to provide pressure within the esophagus orsmall/large intestine. A small gauge for measurement of pressure couldbe a device in accordance with the subject invention.

With these definitions in mind, the subject invention provides a methodof regulating gastrointestinal action in a subject. The method comprisesdetermining an optimum level of total gastrointestinal action in asubject, the total gastrointestinal action including naturally occurringgastrointestinal action and non-naturally occurring gastrointestinalaction; positioning a stimulatory electrode relative to the subject sothat the stimulatory electrode can generate non-naturally occurringgastrointestinal action; positioning a sensor relative to the subject sothat the sensor senses the level of total gastrointestinal action, thesensor being operatively connected to the stimulatory electrode;periodically detecting the level of total gastrointestinal action withthe sensor; and periodically generating non-naturally occurringgastrointestinal action with the stimulatory electrode when the detectedlevel of total gastrointestinal action differs from the optimum leveluntil the detected level of total gastrointestinal action substantiallyequals the optimum level.

The invention further provides a method for reducing weight in a subjecthaving a stomach. The method comprises determining an optimum level oftotal stomach electrical activity in a subject which reduces weight inthe subject, the total stomach electrical activity including naturallyoccurring stomach electrical activity and non-naturally occurringstomach electrical activity; positioning a stimulatory electroderelative to the subject so that the stimulatory electrode can generatenon-naturally occurring stomach electrical activity; positioning anelectrical activity sensor relative to the subject so that theelectrical activity sensor senses the level of total stomach electricalactivity, the electrical activity sensor being operatively connected tothe stimulatory electrode; periodically detecting the level of totalstomach electrical activity with the electrical activity sensor; andperiodically generating non-naturally occurring stomach electricalactivity with the stimulatory electrode when the detected level of totalstomach electrical activity differs from the optimum level until thedetected level of total stomach electrical activity substantially equalsthe optimum level.

Also provided is a method of providing electrical field stimulation to agastrointestinal organ. The method comprises positioning a firststimulatory electrode in a gastrointestinal organ; positioning a secondstimulatory electrode in the gastrointestinal organ, the secondstimulatory electrode being positioned at least about two centimetersfrom the first stimulatory electrode; and electrically stimulating thegastrointestinal organ simultaneously through the first and the secondstimulatory-electrodes, wherein one of the first and the secondstimulatory electrodes has a positive polarity and wherein the other oneof the first and the second stimulatory electrodes has a negativepolarity, thereby providing electrical field stimulation to thegastrointestinal organ between the first and the second stimulatoryelectrodes. In further embodiments, the second stimulatory electrode ispositioned at least about three centimeters, at least about fivecentimeters, or at least about ten centimeters from the firststimulatory electrode.

Additionally provided is a method of providing electrical potentialgradient in a gastrointestinal organ. The method comprises positioning afirst stimulatory electrode in a gastrointestinal organ; positioning asecond stimulatory electrode in the gastrointestinal organ, the secondstimulatory electrode being positioned at least about two centimetersfrom the first stimulatory electrode; and electrically stimulating thegastrointestinal organ simultaneously through the first and the secondstimulatory electrodes, wherein voltage generated by the firststimulatory electrode differs from voltage generated by the secondstimulatory electrode, thereby providing an electrical potentialgradient in the gastrointestinal organ between the first and the secondstimulatory electrodes. In further embodiments, the second stimulatoryelectrode is positioned at least about three centimeters, at least aboutfive centimeters, or at least about ten centimeters from the firststimulatory electrode.

The invention further provides a method of stimulating the vagus nerveof a subject. The method comprises positioning a stimulatory electrodein a gastrointestinal organ of a subject; and generating electricalcurrent in the gastrointestinal organ of the subject with thestimulating electrode, wherein the electrical current in thegastrointestinal organ of the subject stimulates the vagus nerve of thesubject.

The invention also provides a method of placing a device in thegastrointestinal tract of a subject from the exterior of the subject.The method comprises inserting an end of a needle having an interiorbore from the exterior of a subject into the gastrointestinal tract ofthe subject, the gastrointestinal tract of the subject having a centerdefined by a wall, the wall having a thickness defining an interior walladjacent to the center and an exterior wall, and the end of the needlebeing inserted through the wall into the center of the gastrointestinaltract; inserting a device through the interior bore of the needle,wherein the device has an interior wall engaging means and wherein thedevice is inserted at least until the interior wall engaging meansextends beyond the interior bore of the needle; removing the needle; andretracting the device until the interior wall engaging means engages theinterior wall of the gastrointestinal tract of the subject, therebyplacing the device in the gastrointestinal tract of the subject.Alternatively, the invention provides a method of placing a device inthe gastrointestinal wall of a subject from the exterior of the subject.This method comprises inserting an end of a needle having an interiorbore from the exterior of a subject into the gastrointestinal wall ofthe subject, the gastrointestinal wall defining a center of agastrointestinal tract of the subject, the gastrointestinal wall havinga thickness defining an interior wall adjacent to the center and anexterior wall, and the needle being inserted until the end of the needleis positioned in the thickness of the wall between the interior wall andthe exterior wall; inserting a device through the interior bore of theneedle, wherein the device has an engaging means and wherein the deviceis inserted until the engaging means extends beyond the interior bore ofthe needle into the thickness of the wall; removing the needle; andretracting the device until the engaging means engages the thickness ofthe wall, thereby placing the device in the gastrointestinal wall of thesubject.

In one embodiment, the electrical stimulator so placed extendsthroughout the thickness of the wall of the gastrointestinal tract. Forexample, the electrical stimulator can be placed in the stomach of thegastrointestinal tract and can therefore be so placed as to extendthroughout the thickness of the wall of the stomach.

In one embodiment, the interior wall engaging means comprises aplurality of radially extendable arms positioned at an axisperpendicular to the insertion axis of the electrical stimulator. Theelectrical stimulator is inserted until the axis of the plurality ofradially extendable arms extends beyond the interior bore of the needle,at which point the arms radially extend. The electrical stimulator isretracted until the radially extended arms engage the interior wall ofthe gastrointestinal tract.

Materials and Methods

Preparation of Dogs. Healthy female (males are excluded since they wouldwet the jacket during urination) hound-dogs are used in this study. Thedog is chosen to be the model for this study because: 1) the patterns ofgastric myoelectrical activity and motility in dogs are the same asthose in humans; and 2) the canine model has been used for theinvestigation of gastrointestinal motility for many years, andexperimental results indicated that this animal model is ideal formotility studies.

After an overnight fast, the dog is operated upon under anesthesia.Approximately thirty minutes prior to induction of anesthesia, the dogis pre-medicated with acepromazine maleate (2 ml subcutaneously) andatropine (1 mg subcutaneously). Anesthesia is induced with thiamylalsodium (30 ml/kg, intravenously). Following induction of anesthesia andendotracheal incubation, anesthesia is maintained for surgery using 1.5to 2.0% isoflurane in oxygen-nitrous oxide (1:1) carrier gases deliveredfrom a ventilator (15 breaths/min with a titred volume of about 15ml/kg). The animal is monitored with the assessment of tissue color andpulse rate. Four pairs of bipolar recording electrodes (cardiac pacingwires) are implanted on the serosal surface of the stomach along thegreater curvature at an interval of 4 cm (see FIG. 16). The most distalpair is 2 cm above the pylorus. The distance between the two electrodesin a pair is 0.5 cm. Teflon-insulated wires are brought out through theabdominal wall subcutaneously and placed under a sterilized dressinguntil needed for recording and stimulation studies. Three strain gaugesare placed, one in the fundus, one in the proximal antrum, and the otherin the distal antrum, for the measurement of fundic tone and antralcontractions. The wires of these strain gauges are brought out the sameway as the electrodes. An intestinal fistula is made in the duodenal (20cm beyond the pylorus). The fistula is used for the assessment ofgastric emptying of liquids.

Following completion of surgery, the anesthetic gases are discontinued,and ventilation is continued with oxygen until the dog regains airwayreflexes and is extubated. After extubation, the dog receivesmedications for post operative pain control and is transferred to arecovery cage. All studies are initiated about ten days after surgerywhen the dogs have completely recovered. A dog jacket and protectiveplastic collar are worn all the time to protect the wires and cannulafrom being chewed out by the dog.

Measurement and analysis of gastric slow waves. The gastric slow waveare measured from the implanted serosal electrodes using a multi-channelrecorder (Acknowledge, Biopac Systems, Inc., Santa Barbara, Calif.). Allsignals are displayed on a computer monitor and saved on the hard diskby an IBM- compatible 486 PC. The low and high cutoff frequencies of theamplifier are set at 0.05 Hz and 10 Hz respectively. The data is sampledat 20 Hz. For the spectral analysis of the slow waves, all data isfurther lowpass filtered with a cutoff frequency of 1 Hz (Qian et al.1999; Abo et al. 2000).

Percentage of normal slow waves: The percentage of normal slow waves isdefined as the percent of time during which regular slow waves (3.5-7.0cpm) are detected from the time-frequency analysis of the slow wavemeasurement. This parameter reflects the regularity of gastric slowwaves and is computed using the time-frequency analysis method discussedbelow (see also Chen et al. 1993). In the outcome-basedfeedback-controlled RGES system, this parameter is on-line computed andused to control the strength of stimulation.

Percentage of slow wave coupling: This parameter represents thecoordination or coupling of gastric slow waves measured from differentregions of the stomach. It is defined as the percentage of time duringwhich the recorded slow waves in different regions are coupled. Across-spectral analysis method is used to calculate the percentage ofslow wave coupling among the different channels. First time-frequencyanalysis is performed on each channel minute by minute and the frequencyof each minute of the slow wave in each channel is determined. Secondly,the frequencies of the slow waves between any two channels are compared.The minute of the slow waves recorded on the two channels is defined ascoupled if their dominant frequencies are both within the normalfrequency range and their difference is <0.2 cpm.

Measurement and analysis of gastric contractions. Gastric contractionsin the fundus, proximal antrum and distal antrum are measured using thesurgically implanted strain gauges as shown in FIG. 16. The recordingsare made using the same multi-channel recorder used for the electricalrecordings. Computerized software computes the frequency of contractionsand the strength of contractions (area under the curve of eachidentified contraction).Measurement and analysis of vagal activity. Regular electrocardiogram(ECG) is recorded using abdominal surface electrodes. R-R intervals arederived from the ECG using a method of fuzzy neural network. A signal,called heart rate variability (HRV), is derived after interpolation andsampling. Smoothed power spectral analysis is then performed on the HRVsignal. Two parameters are computed from the power spectrum: LF (areaunder the curve in the low frequency band (0.04-0.15 Hz)) and HF (areaunder the curve in the high frequency band (0.15-0.50 Hz)). It is wellestablished that the LF reflects mainly sympathetic activity and partialvagal activity, where the HF represents purely vagal activity (Lu et al.1999). In addition, the ratio, LF/HF, represents sympatho-vagal balance.Measurement of “symptoms” in dogs. The symptoms of the dog during theexperiment to be evaluated include salivation, licking tongue, murmuring(whine, growl, bark, yelp), and moving due to discomfort, and are scoredby their severity and/or frequency. The severity is classified into 4degrees, none (0), mild (1), moderate (2), and severe (3). Forsalivation, none is 0, seen around mouth is 1, sometimes drop is 2, andcontinuously drop is 3. For licking tongue and murmuring, none is 0,seldom/seen for <25% time of study is 1, often/seen for <50% time ofstudy is 2, and severe/seen for >50% time of study is 4. For movementdue to discomfort, none/same as baseline is 0, mild/seen but no need tosoothe is 1, moderate/seen and need to soothe is 2, and severe/dogjumps, or moves constantly to interrupt study is 3. Vomiting is notedseparately and scored as 4. A total symptom score is calculated.

EXAMPLE I

Antegrade Electrical Stimulation

Extensive experiments on antegrade gastric and intestinal electricalstimulation have been performed in both animals and humans. Unlike theretrograde stimulation proposed in this application, these studies weredesigned to normalize impaired gastrointestinal motility. The mostimportant points learned from these experiments are: 1) electricalstimulation is able to entrain slow waves; 2) antegrade stimulationaccelerates gastric emptying; and 3) no adverse effects have been notedin these previous studies, demonstrating safety of electricalstimulation.

Antegrade electrical stimulation entrains slow waves. A number of recentsystematic studies have been performed and indicated that a completeentrainment of gastric slow waves is feasible in both humans and dogs(Lin et al. 1998; Lin et al. 2000a; McCallum et al. 1998; Qian et al.1999; Abo et al. 2000; Lin et al. 2000b). The pulse width used for theentrainment of gastric slow waves in patients with gastroparesis wasabout 300 ms. However complete entrainment is limited to a pacingfrequency of slightly higher than the intrinsic frequency of the gastricslow wave. The entrainment was 100% when the pacing frequency was 10%higher than the intrinsic frequency and dropped to about 70% when thepacing frequency was 30% higher. In addition, the maximal drivenfrequency was about 4.3 cpm in patients with gastroparesis (Lin et al.1998).

Antegrade electrical stimulation normalizes dysrhythmia. Entrainment ofgastric slow waves using electrical stimulation with long pulses (in theorder of milliseconds) makes it possible for the normalization ofgastric dysrhythmia. Recent canine studies have also shown that gastricelectrical stimulation was able to normalize gastric dysrhythmia inducedby various pharmacological agents, such as vasopressin, glucagon andatropine (Qian et al. 1999). FIGS. 4A-4C show a typical example ofimpaired gastric slow waves (bradygastria, FIG. 4A) induced by atropineand normalized slow waves after gastric pacing (FIG. 4C).

In addition to gastric entrainment, it has also been shown thatintestinal slow waves can be entrained using intestinal pacing with longpulses (Lin et al. 2000a; Lin et al. 2000b).

Antegrade electrical stimulation accelerates gastric emptying inpatients with gastroparesis. The effect of electrical stimulation ongastric emptying and symptoms in patients with severe gastroparesis hasbeen investigated (McCallum et al. 1998). Electrical stimulation wasperformed via serosal electrodes implanted on the proximal stomach. Aportable external pacemaker was built and used for stimulation for onemonth or more in each patient. A significant improvement was observed inboth gastric emptying (FIG. 5) and symptoms of nausea, vomiting,bloating and etc.

Gastrointestinal electrical stimulation does not induce any adverseevents. The above study not only suggested the therapeutic potential ofantegrade gastric electrical stimulation for gastroparesis but alsodemonstrated the safety of gastric electrical stimulation in humans. Noside effects or adverse events were noted in this clinical study. Chenand his colleagues have performed gastrointestinal electricalstimulation in more than 15 patients with gastroparesis and more than 30dogs over the course of 7 years (Lin et al. 1998; Lin et al. 2000a;McCallum et al. 1998; Qian et al. 1999; Abo et al. 2000; Lin et al.2000b). No adverse events have been observed in the patients. Some ofthe patients were studied for more than 4 months. Similarly, nogastrointestinal symptoms, such as vomiting or diarrhea, or othersymptoms have been observed in dogs. Autopsy was performed in every dogthat was sacrificed at the end of the study. No scars or muscle damagewere noted in the gastric or intestinal area where stimulationelectrodes were sutured. Some of the dogs have been studied for a periodof 6 months or more.

EXAMPLE II

Retrograde Electrical Stimulation (RGES) for Treatment of Obesity andOther Gastrointestinal Tract Disorders

This example places an artificial ectopic pacemaker in the distal antrumto partially or completely override regular gastric slow waves with afeedback control mechanism. Two pairs of bipolar electrodes are placedon the serosa along the greater curvature laparoscopically. The distalpair is about 2 cm above the pylorus and is used for electricalstimulation (serving as an artificial pacemaker), whereas the proximalpair is about 10 cm above the pylorus and is used for the measurement ofgastric slow waves. The regularity of gastric slow waves is calculatedfrom the proximal pair and the strength of electrical stimulationapplied on the distal pair is determined based on the regularity ofgastric slow waves measured from the proximal pair. The targetingregularity is set up in the initial trial period such that the intake offood is reduced but the subject is free of any symptoms other than earlysatiety. Once this value is determined, the value is used toautomatically control the strength of electrical stimulation.

The principle of RGES is the opposite of what has been described forpatients with impaired gastric emptying. RGES employs retrograde pacingwith the aim of retarding the propulsive activity of the stomach andslowing down gastric emptying (FIG. 2). By slowing down gastric emptyingof ingested food from the stomach, a sense of feeling full (satiety)results, leading to a reduction in food intake and subsequent weightloss.

The rationale behind RGES at a tachygastrial frequency is toelectrically induce tachygastria in the distal stomach, in effectproducing an artificial ectopic pacemaker. This artificial pacemaker hastwo functions: 1) it interrupts the normal distal propagation of regularslow waves; and 2) it paces the gastric slow waves in the distal stomachat a tachygastrial rhythm. Both of these effects result in an absence ofcontractions in the distal stomach (see FIG. 3) and cause delayedgastric emptying. This results in increased satiety and decreased foodintake. This method allows adjustment of the strength of electricalstimulus, and hence the degree of impairment in the gastric slow waveand its propagation. Thus, with proper settings, the amount of foodintake can be finely tuned.

RGES at a “physiological” frequency reduces food intake. A study wasperformed to investigate the effects of RGES on gastric emptying andfood intake. The study was performed in 10 healthy dogs with chronicallyimplanted 4 pairs of serosal electrodes along the greater curvature: the3 proximal pairs recorded gastric slow waves and the most distal pair (2cm above the pylorus) provided retrograde stimulation. Each dog wasstudied in 3 sessions, without electrical stimulation (session 1), withstrong retrograde stimulation to induce vomiting or noticeable symptoms(session 2) and with mild retrograde stimulation that does not inducevomiting or clearly noticeable discomfort (session 3). Electricalstimulation was performed at a frequency 10% higher than the intrinsicfrequency of gastric slow waves measured at baseline. The dogs weregiven unlimited access of food during the study. All observable symptomswere noted and graded.

RGES resulted in a significant reduction in food intake (FIG. 6). Withstrong retrograde stimulation (session 2), eight dogs vomited and alldogs showed various symptoms (see Materials and Methods). On the otherhand, with mild stimulation (session 3), while inducing no vomiting andno significant increase in the score of other observable symptoms, foodintake was significantly reduced (FIG. 7).

This study demonstrates that RGES with appropriate stimulus is able toreduce food intake without inducing discomfort or vomiting.

RGES at a “physiological” frequency also impairs slow wave propagationand delays gastric emptying. In addition to the above study, the effectof RGES at a normal frequency on gastric slow waves and gastric emptyingwas investigated in a separate study (Lin et al. 1999). The experimentwas performed in 6 dogs implanted with gastric serosal electrodes asbefore and equipped with a duodenal cannula for the assessment ofgastric emptying (see Materials and Methods). After the ingestion of aliquid meal, electrical stimulation was performed via the distalelectrodes with a frequency of 10% higher than the intrinsic frequencyof the gastric slow wave. It was found that gastric emptying (30 minutesafter eating) was significantly delayed with RGES in comparison with thecontrol session (FIG. 8A). This was accompanied by a significantimpairment in gastric slow wave coupling (see Materials and Methods)(FIG. 8B).

This study suggests that the reduction in food intake observed in thefeasibility study presented above is attributed to the impairment ingastric emptying and gastric slow wave propagation.

RGES at a tachygastrial frequency inhibits gastric contractions. WhileRGES at a physiological frequency is effective in delaying gastricemptying and reducing food intake, it is limited in its practicalutility because of the high level of energy required. The stimulationpulse width used is about 300-500 ms which is about one thousand timeshigher than that in cardiac pacing, implying a substantial amount ofenergy consumption. To overcome this energy consumption issue, RGES at atachygastrial frequency can be used to achieve the same effects asabove. A lower, and possibly much lower, energy is required for RGES ata tachygastrial frequency than for RGES at a normal frequency. RGES attachygastrial frequency is even more efficient because it not onlyimpairs distal propagation of gastric slow waves but also inducestachygastria in the stomach and further reduces gastric contractions.

In a further experiment, a dog was implanted with 4 pairs of gastricserosal electrodes along the greater curvature and a strain gauge closeto the most distal pair of electrodes (2 cm above the pylorus). RGES wasperformed using the third pair of electrodes (6 cm above the pylorus) ata frequency of 11 cpm (the intrinsic frequency in the dog was about 6cpm) and a pulse width of 50 ms. As shown in the left half of FIG. 3,normal distally propagated slow waves (top 4 tracings) and regulargastric contractions (bottom tracing) were observed at baseline. Afterstimulation (right half of FIG. 3), however, the frequency of gastricslow wave in channel 4 was increased and gastric contractions werediminished. This experiment was repeated several times in the same dogwith the same results.

In the RGES procedure, each dog undergoes gastrointestinal pacing duringat least 3 separate sessions. These include a “control” session (nostimulation), a “pacing” session (electrical stimulation resulting in acomplete entrainment of gastric slow waves in at least one channeladjacent to the stimulation electrodes is called “pacing”), and one ormore “optimization” sessions with stimulation energy reduced from thepacing session. Two consecutive sessions are at least 3 days apart.

The protocol for the control session (no electrical stimulation) is asfollows (sequentially): a 30-min baseline recording, 30-min with accessto unlimited regular solid food (the same food used in daily care of theanimal) and water, 60-min postprandial recording after the removal ofthe food and water.

The protocol for the pacing session is composed of 30-min baselinerecording, 15-min RGES, 30-min with access to unlimited food and waterwith RGES, 60-min postprandial recording with RGES after the removal offood and water. Electrical stimulation parameters are chosen tocompletely entrain gastric slow waves in the channel adjacent to thestimulation electrodes. Based on the experiments, the followingparameters are able to entrain gastric slow waves: stimulationfrequency—13 cpm (the normal frequency in the dog is about 5-6 cpm);pulse (square wave) width—500 ms; and pulse amplitude—4 mA (constantcurrent is used in all experiments). A small adjustment is necessary foreach particular dog and this is done at the beginning of stimulation byvisually inspecting whether the paced slow waves are phase-locked withthe stimulus.

The protocol for the optimization sessions is the same as the “pacing”session. However, electrical stimulation is performed with a reducedenergy. More than one session is required to optimize the performance ofGRES by changing stimulation parameters. The definition of optimizationis based on an optimal combination of efficacy, safety and feasibility.That is, the optimal RGES settings are those that result in asignificant reduction in food intake (efficacy) but do not induceundesired symptoms, such as nausea or vomiting (safety) with minimalenergy (maximally feasible for an implantable device). Iterativeadjustments of stimulation parameters are made to achieve this result.

Measurements made during the entire experiment include: food intake, allobservable “symptoms”, gastric myoelectrical activity, gastriccontractions (including fundic tone), gastric compliance, andelectrocardiogram. A detailed description of the measurements andanalyses of these parameters is provided under the Materials and Methodssection.

Analysis of variance (ANOVA) is performed to study the difference infood intake and symptom score (quantitative analysis is described underMaterials and Methods) among the control, pacing and stimulationsessions. Effects of RGES on gastric slow waves and gastric contractionsis also assessed.

The “pacing” session results in a substantial reduction of food intakebut moderate to severe symptoms, such as vomiting. The optimalstimulation session results in a similar reduction of food intake withabsolutely no vomiting, and no significant increase in other symptoms incomparison with the control session. The ideal result is a significantand substantial reduction in food intake with absolutely nouncomfortable symptoms and minimal consumption of energy (comparablewith that in cardiac pacing).

By contrast with conventional methods of electrical stimulation, thisRGES system contains two important additional elements: detection of theoutcome of stimulation; and automated control of stimulation based on apre-determined target (or “prescription”). The pre-determined target isthe percentage of impairment of slow waves (=100%−% normal 3.5-7.0 cpmslow waves) measured by the sensing electrodes.

FIG. 12 presents the block diagram of the system. The gastric slow waveis recorded with cutoff frequencies of 0.5 to 12 cpm by the sensingelectrodes placed in the middle stomach and digitized at a frequency of1 Hz (60 cpm). The digitized signal is subjected to digital signalprocessing. Since the recording of gastric slow waves may containstimulation artifacts, the recording is first processed for thecancellation of stimulation artifacts with an adaptive filter using therecursive least squares (RLS) algorithm. Time-frequency analysis isperformed on the artifacts-free gastric recording by the time-frequencyanalyzer and the percentage of normal gastric slow waves (or thepercentage of impairment) is computed from the time-frequencyrepresentation. This percentage of impairment is then compared with thetargeted impairment by a digital controller. If the computed percentageis within the range of ±5% of the target, the stimulation is maintainedwithout any modification. If the computed percentage of impairment islower than the target minus 5%, the stimulation energy or pulse width isincreased by 10% or a smaller or larger step to be determined byexperiments. If the computed percentage of impairment is higher than thetarget plus 5%, the pulse width is reduced by 10% or a smaller or largerstep to be determined by experiments. The digital stimulus is convertedinto an analog signal by a D/A converter. A constant current controlcircuit is used to guarantee that constant current is delivered to thestimulation electrodes placed 2 cm above the pylorus.

Maximal and minimal thresholds for pulse width are determined byexperiments and pre-set. An alarm is set off if one of the thresholds isreached and the stimulation is switched to a fixed parameter mode (usingoptimized parameters derived as discussed above). The maximal thresholdis used to protect the subject from being hurt with excessivestimulation. The minimal threshold is introduced to protect the systemfrom being ineffective and would be reached in two instances: 1) if thesystem malfunctions; and 2) if the percentage of normal gastric slowwaves before stimulation in the subject is below the targetedimpairment. Five minutes after stimulation with the fixed mode, theautomatic system is turned on again.

The RGES system has the following advantages: 1) the stimulation is notfixed but dynamically modulated by the outcome of stimulation. It ismuch easier to optimize the performance in individual subjects than bythe somewhat random process of using fixed parameters; 2) the physiciancan actually “prescribe” the “dosage” of treatment. For example, ahigher “dosage” (higher percentage of impairment) may be “prescribed” atthe beginning of treatment to loose sufficient weight, followed with alower “dosage” to maintain weight loss.

Cancellation of stimulation artifacts. Electrical stimulation artifactsare often superimposed on the gastric slow wave recording. Theseartifacts must be cancelled before the time-frequency analysis of thegastric slow wave. Otherwise, the computed percentage of impairment ornormal 3.5-7.0 cpm slow waves would be inaccurate. Similar problems havebeen encountered and adaptive filtering has been applied for thecancellation of respiratory artifacts superimposed on the abdominalsurface recording of gastric slow waves (Chen et al. 1989) or intestinalslow waves (Chen and Lin 1993).

The similar technique of adaptive filtering is used with RGES to cancelthe stimulation artifacts. As shown in FIG. 13, d_(j) represents themeasurement of gastric slow waves by the sensing electrodes. It containsgastric slow waves (s_(j)) and stimulation artifacts (n_(j)). Areference signal x_(j) is obtained directly from the stimulator. It isclear that this reference signal is closely correlated with thestimulation artifact, n_(j), but may have a different phase andamplitude. An adaptive filter (AF) is used to adjust the amplitude andphase of the reference signal such that its output y_(j) is identical tostimulation artifacts, n_(j). Consequently, the subtracted output e_(j)would be artifacts-free.

Various algorithms available for the adaptive filter can be used in thismethod, including least mean squares algorithm and recursive leastsquares (RLS) algorithm. The selection of the algorithm is based on theperformance and the computational feasibility for an implantable device.An RLS algorithm is a good choice.

Time-frequency analysis of gastric slow waves. Numerous methods areavailable in the literature for time-frequency analysis (Akay 1995).Short-time Fourier transform (STFT) is among the early works in thisarea. A sliding window with a short length is used in the STFT and thesignal inside the window is assumed to be stationary. Wigner developedanother approach (Wigner 1932) which was later adapted to signalprocessing by Ville (1948). In this case, a quadratic distribution ofthe time and frequency characteristics of the signal is derived. Themajor drawback of this representation is in its interpretation. That is,the representation not only contains the signal components but alsointerference terms, called cross-terms, generated by the interaction ofthese signal components with each other. Many suggestions have been madeto improve the Wigner-Ville distribution, all using some kind offiltering process to enhance the signal components and to attenuate theinterference terms. The exponential distribution proposed byChoi-Williams was one of them (Choi and Williams 1989). Cohen (1992)unified the quadratic time-frequency representations. He showed thatmost of them belonged to a general class, in which each member wasgenerated by the choice of an appropriate kernel function. In the early1980s, a theory that unified a set of ideas about analyzing a signal atdifferent resolutions was proposed and was called wavelet representation(Rodet 1985; Grossman and Morlet 1984). An interesting characteristic ofthis method relies on its ability to behave like a mathematicalmicroscope, that is, it can zoom in on short-lived signal components.The wavelet transform (WT) is a signal decomposition on a set of basisfunction, obtained by dilations, contractions, and shifts of a uniquefunction, the wavelet prototype. A basic distinction between WT and STFTis that while the basic functions of the latter consist of a function ofconstant width translated in time and filled in with high-frequencyoscillations, the former has a frequency-dependent width. In otherwords, it is narrow at high frequencies and broad at low frequencies.This gives the WT the ability to zoom-in on transitory phenomena, whichare usually short-lived components of a signal.

Each of the above mentioned methods has been applied to thetime-frequency representation of the gastric slow wave measured fromelectrogastrography. The STFT method was first introduced and is stillbeing used by various investigators (Chen and McCallum 1995). With theEGG (electrogastrogram, abdominal surface measurement of gastric slowwaves) signal sampled at 1 Hz, the STFT is typically performed with awindow length of about 4 minutes and a shift of 1 minute between twoconsecutive Fourier transforms. The disadvantage of this method is itslow temporal resolution. Abnormal slow waves with a brief duration cannot be reliably detected.

The Wigner distribution and the exponential distribution wereinvestigated (Lin and Chen 1994). The unmodified Wigner distribution wasfound inappropriate for the time-frequency analysis of the EGG due toinherent interference terms resulting from noises and interferencepresent in the EGG. The exponential distribution provided much betterperformance than the Wigner distribution but was not satisfactory,especially when the EGG signal was noisy (Lin and Chen 1994). Itsperformance in the analysis of the gastric slow wave measured from theimplanted serosal electrodes is expected to be better since the serosalrecording does not contains much noise or artifacts. The WT method wasrecently applied in an attempt to identify contraction-related spikepotentials in the EGG. However, no convincing data have been provided,suggesting that spike potentials are present in the EGG and that theycan be detected using the WT method. In addition to these methods, aso-called adaptive spectral analysis method was developed which is basedon the autoregressive moving average (ARMA) model and was implementedusing an adaptive ARMA filter (Chen et al. 1990).

The various methods for the time-frequency analysis (or running spectralanalysis) of the cutaneously recorded gastric slow waves (Chen et al.1990; Chen et al. 1993; Lin and Chen 1994; Lin and Chen 1995; Wang etal. 1998; Lin and Chen 1996), or electrogastrography (EGG), aresummarized as follows:

Autoregressive moving average (ARMA) modeling with adaptive filtering.Gastric slow waves can be detected noninvasively using abdominal surfaceelectrodes, a method called electrogastrography. The cutaneousmeasurement and display of gastric slow waves is called anelectrogastrogram (EGG). The EGG contains elements of both gastricsignal and noise (or interference) such as respiratory and motionartifact. Spectral analysis methods are used to derive clinically usefulparameters from the EGG. Time-frequency analysis methods have beendeveloped or applied for the quantitative assessment of the regularityof gastric slow waves. The most frequently used parameter, thepercentage of normal slow waves, was first proposed by Chen (Chen andMcCallum 1995; Chen et al. 1995a). It is defined as the percentage oftime during which normal gastric slow waves (2-4 cpm in humans and3.5-7.0 cpm in dogs) is detected from the time-frequency analysis of theEGG. This same parameter is used to provide feedback control of thestrength of RGES in the subject method.

The first method of time-frequency analysis developed by Chen was calledadaptive spectral analysis (Chen et al. 1990). It is based on anautoregressive moving average (ARMA) model and implemented using anadaptive ARMA filter. The parameters of the adaptive ARMA filter areadapted each time when a new sample is available using the least meansquare (LMS) algorithm. The instantaneous frequency of the signal iscomputed from the filter parameters based on the ARMA model. This methodhas been refined and used for numerous years (Chen and McCallum 1995;Chen et al. 1995a; Chen et al. 1993; Lin and Chen 1996; Chen andMcCallum 1991). It is adaptive, robust and relatively simple incomputation.

Choi-William exponential distribution. The second method for thetime-frequency analysis of the EGG was the Choi-William exponentialdistribution (Lin and Chen 1994). This method was introduced by Choi andWilliams (1989). It is a new distribution with an exponential-typekernel, which they called exponential distribution. This method wasinitially developed to solve the problem of cross-terms generated by theWigner distribution. An optimal performance may be obtained for aparticular application by a tradeoff between cross-term suppression andauto-term reduction. Experimental data with the EGG show that thismethod provides a good performance when the EGG has a highsignal-to-noise ratio. The performance is not satisfactory when the EGGis corrupted with noises and interference.

Overcomplete signal representation. Traditionally, a signal isrepresented using an expansion of a particular orthogonal basis, such asFourier basis, discrete cosine basis and wavelet basis, and the numberof expansion is chosen such that the representation is unique. Thisrepresentation is called complete signal representation. In contrast tocomplete signal representation, overcomplete signal representation usesa higher number of bases than the number of frequency components of thesignal. Most recently, the concept of overcomplete signal representationhas been applied for the time frequency analysis of the gastric slowwave and two algorithms have been proposed for the optimization of theovercomplete signal representation. One algorithm is the fast algorithmof matching pursue and the other is based on an evolutionary program(Wang et al. 1998). In addition, the so-called minimum fuel model wasutilized and a special neural network was developed for it to optimizeovercomplete signal representation.

Selection of the time-frequency analysis method. Selection of thetime-frequency analysis method to be used in the RGES system is based onthe following criteria: 1) reliability and robustness; 2) accuracy; and3) feasibility. A comparison among various time-frequency analysismethods was previously made (Lin and Chen 1995). The adaptive spectralanalysis method is probably the best for this RGES system. It isreliable and robust. Its accuracy has been validated in severaldifferent studies (Chen et al. 1993 80; Chen and McCallum 1991). It usesthe least mean square (LMS) algorithm (simple in computation), whichmakes it very feasible to be incorporated into an implantablestimulator. Other methods, such as STFT, exponential distribution andWT, can be investigated in comparison with the adaptive spectralanalysis method. The over-complete signal representation method isprobably too complicated for an implantable device (Wang et al. 1998).

Adaptive Spectral analysis is based on the autoregressive moving average(ARMA) model. In this method, it is assumed that a signal S_(n) (n: timeinstant) can be generated by exciting an ARMA process using a randomtime series, n_(n). Mathematically, it can be written as follows:

$S_{n} = {{- {\sum\limits_{k = 1}^{p}{a_{k}s_{n - k}}}} + {\sum\limits_{k = 1}^{q}{c_{k}n_{n - k}}} + n_{n}}$where a_(k) (k=1, 2, . . . , p) and c_(k), (k=1, 2, . . . q) are calledthe ARMA parameters. The power spectrum of the signal, s_(n), can becalculated from these ARMA parameters.

To model a real signal x_(n), one simply proceeds in the oppositedirection. By constructing a so-called adaptive ARMA filter (see FIG.14, z⁻¹ stands for one sample delay), the output signal, y_(n), now canbe made to approximate the input signal, x_(n). It is expressed as:

$y_{n} = {{\sum\limits_{k = 1}^{p}{a_{k,n}x_{n - k}}} + {\sum\limits_{k = 1}^{q}{c_{k,n}e_{n - k}}}}$where a_(k,n) and c_(k,n) are time-varying parameters and e_(n) is theestimation error:e _(n) =x _(n) −y _(n)

The ARMA parameters are initially set as zeros and iteratively adjustedby the least mean squares (LMS) algorithm, expressed as follows:c _(k,n+1) =c _(k,n)+2μ_(c) e _(n) e _(n) −k, k=1, 2, . . . , qa _(k,n+1) =a _(k,n)+2μ_(a) e _(n) e _(n) −k, k=1, 2, . . . pwhere step-sizes, μ_(a) and μ_(c), are small constants controlling theadaptation speed of the LMS algorithm (Chen et al. 1993). The algorithmstates that the filter parameters at each successive time step,a_(k,n+1) and c_(k,n+1), are equal to their current values, a_(k,n) andc_(k,n), plus a modification term. The number of the filter parametersused is equal to q+p. The best value for q may be associated withspecific applications. The value of p must be greater than or equal tothe number of digitized points that span the longest rhythmic cycle ofinterest in a signal. For example, if the period of the rhythmiccomponent of interest in a signal is 20 seconds (0.05 Hz or 3.0 cpm) andthe sampling frequency is 2 Hz, the smallest value of p should be 40.This requirement of this large value is attributed to the nature of theLMS algorithm.

Once the adaptive filter converges, the power spectrum of the inputsignal x_(n), can be calculated from the filter parameters. At any pointin a time series, a power spectrum can be calculated instantaneouslyfrom the updated parameters of the model. Similarly, the power spectrumof the signal for any particular time interval can be calculated byaveraging the filter parameters over that time interval.

The implementation of the RGES system in a portable device is shown inFIG. 15. It contains similar components as those shown in FIG. 13. A newelement of the RGES stimulator is the addition of a DSP (digital signalprocessing) controller.

EXAMPLE III

Portable stimulators for gastric electrical stimulation are feasible andeffective. A portable electrical stimulator was previously developed(Chen et al. 1995b) and used in more than 20 patients (see FIG. 9). Thestimulator uses fixed parameters and delivers stimulation pulses with afrequency of 3 cpm, pulse width of 300 ms and pulse amplitude of 4 mA(constant current mode). The constant current is guaranteed with a loadin the range of 300-1000 W. The stimulator is operated by a 9-voltbattery with an easy access for replacement. A female pin is availableto connect the stimulator with the stimulation electrode wire. There isa manual switch for turning on or off the stimulator. This stimulatorhas been used in a clinical research study (McCallum et al. 1998) withno malfunction or adverse events reported.

EXAMPLE IV

Electrical Field Stimulation

This example illustrates the entrainment of gastric slow waves and theacceleration of gastric emptying using gastric electrical fieldstimulation. Two electrodes are placed on the serosa of the stomach.Unlike the bipolar or monopolar methods of the prior art, one electrodeis placed in the proximal stomach and the other in the distal stomach.The proximal electrode has a positive polarity, and the distal one has anegative polarity. Electrical stimulation is performed via these twoelectrodes. The stimulation frequency is 10% higher than the naturalfrequency of the gastric slow waves. Instead of single pulses, a trainof pulses with a frequency in the range of 1 to 50 Hz is used for eachstimulus.

By placing the two stimulator electrodes in the gastric cardiac areaclose to the lower esophageal sphincter (LES), the methods can be usedfor the treatment of gastric esophageal reflux (by increasing the LESpressure) or achalasia (by relaxing the LES).

EXAMPLE V

Electrical Field Stimulation of the Vagus Nerve—gastric ElectricalStimulation Affects Vagal Efferent Activity in Dogs. Evidence of aneffect of gastric electrical stimulation on vagal activity is providedin this Example. These studies were performed in 5 healthy female hounddogs implanted with one pair of serosal electrodes on the greatercurvature 2 cm above the pylorus. The experiment was performed in thefasting state after a complete recovery from surgery. The protocolconsisted of 30-min baseline, 30-min stimulation and 30-min recovery.The stimulus was composed of a series of pulse trains. The pulse trainwas on for 2 seconds and off for 3 seconds. The pulse in each train hada frequency of 40 Hz, a pulse width of 200 us and an amplitude of 4 mA.A significant increase in the ratio of sympathetic and vagal activities(assessed using the spectral analysis of the heart rate variabilitysignal as described) was observed with RGES (0.93±0.49 with GRES incomparison with 0.67±0.49 (p<0.04) at baseline). This increase wasattributed to an decrease in the percentage of vagal activity (40.6±9%vs. 54±12%, p=0.06) and an increase in the percentage of sympatheticactivity (39±12% vs. 31±14%, p<0.05) (see FIG. 11)(Wang et al. 2000b).

In another experiment (Wang et al. 2000a), the effect of differentstimulation frequencies on vagal efferent activity in 5 dogs wasinvestigated using antegrade gastric electrical stimulation. It wasfound that stimulation at a physiological frequency enhanced vagalefferent activity, whereas stimulation at a tachygastrial frequencyinhibited vagal efferent activity.

EXAMPLE VI

Placement of Electrodes

This example illustrates a method for the placement of electrodes in thegut without any surgical intervention. The prior art methods ofelectrode placement generally involve the implantation of electrodes onthe serosa of the gut via open surgery or laparoscopic surgery. Generalanesthesia and hospital stay are necessary.

In this example, electrodes are placed via endoscopy without generalanesthesia or hospital stay. First, the conscious patient is sedated andan endoscope is inserted into the stomach or small intestine via themouth. This step is optional, and is for the purpose of observing theplacement of the electrodes. Then, a sharp, long and small needle with ahole in the middle (the same needle used for the placement ofpercutaneous endoscopic gastrostomy tubes) is inserted into the stomachor small intestine. A teflon-isolated wire is then inserted into thestomach or small intestine via the hole of the needle under endoscopy.The teflon at the distal portion of the wire is peeled off so that theexposed portion of the wire serves as an electrode. There are barbsarranged circumferentially at the end tip of the wire. The needle isremoved after the insertion of the wire. The wire is slowly pulled backuntil the barbs contact the mucosa and stop the wire from being furtherpulled out. The wire on the abdomen is attached to the abdominal skinand protected from infection. Various numbers of wires can be placed inthis manner, without the need to hospitalize the patient. Therefore, thepatient can be discharged after a few hours of recovery from sedation.

The monitoring and electrical stimulation of the colon can also be done,with the electrodes being placed in a similar manner but viacolonoscopy.

Although preferred embodiments have been depicted and described indetail herein, it will be apparent to those skilled in the relevant artthat various modifications, additions, substitutions and the like can bemade without departing from the spirit of the invention and these aretherefore considered to be within the scope of the invention as definedin the claims which follow.

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What is claimed is:
 1. A method of placing a device in thegastrointestinal tract of a subject from the exterior of the subject,the method comprising: inserting an end of a needle having an interiorbore from the exterior of a subject into the gastrointestinal tract ofthe subject, the gastrointestinal tract of the subject having a centerdefined by a wall, the wall having a thickness defining an interior walladjacent to the center and an exterior wall, and the end of the needlebeing inserted through the thickness of the wall; inserting a devicewith an insertion axis through the interior bore of the needle, whereinthe device has an engaging means comprising a plurality of radiallyextendable arms positioned at an axis perpendicular to the insertionaxis, and wherein the device is inserted at least until the engagingmeans extends beyond the interior bore of the needle; removing theneedle; and retracting the device until the plurality of radiallyextendable arms positioned at an axis perpendicular to the insertionaxis engages the interior wall of the gastrointestinal tract of thesubject, thereby placing the device in the gastrointestinal tract of thesubject.
 2. The method of claim 1, wherein the device is a stimulatoryelectrode.
 3. The method of claim 1, wherein the device is operativelyconnected to a sensor.
 4. The method of claim 1, wherein the pluralityof radially extendable arms positioned at an axis perpendicular to theinsertion axis engages the interior wall of the gastrointestinal tractof the subject, thereby placing the device in the center of thegastrointestinal tract of the subject.
 5. The method of claim 1, whereinthe method further comprises viewing the gastrointestinal tract of thesubject via endoscopy or colonoscopy.
 6. The method of claim 1, whereinthe step of inserting the device is observed endoscopically via anendoscope placed in the stomach through the mouth, or via a colonoscopeplaced in the small intestine.
 7. The method of claim 1, wherein themethod occurs without the use of general anesthesia.
 8. A method ofplacing an antegrade gastrointestinal stimulatory device with aninsertion axis and an engaging means comprising a plurality of radiallyextendable arms into a subject's gastrointestinal tract from theexterior of the subject, the method comprising: inserting the end of aneedle having an interior bore into the subject's gastrointestinaltract, the gastrointestinal tract having a center defined by a wall, thewall having a thickness defining an interior wall adjacent to the centerand an exterior wall, and the end of the needle being inserted throughthe thickness of the wall; inserting the device through the interiorbore of the needle until the engaging means extends beyond the interiorbore of the needle; removing the needle; and retracting the device untilthe plurality of radially extendable arms engages the interior wall ofsubject's gastrointestinal tract.